Rationalizing the dosage of phytopharmaceuticals for children by extrapolating adult pharmacokinetic data using PBPK modeling: St. John’s Wort as example

Herbal medicinal products (HMPs) are effective and safe therapeutic options for children. However, many HMPs approved for the treatment of adults are under-researched in pediatric populations. Therefore, off-label use is widespread [ 1 ]. This study aimed to develop and evaluate a physiologically-based pharmacokinetic (PBPK) model for adults (PK-Sim ®​ , OSP Suite) with hypericin from Hypericum perforatum as a model compound using published pharmacokinetik data from different extracts [ 2 ] [ 3 ]. The PBPK model has the potential to close knowledge gaps regarding pharmacokinetic properties of the compound and further the St. John’s Wort extracts. It allows prediction of drug exposure in pediatrics based on age-related physiological differences by extrapolation of adult data. To establish a valid PBPK model, the following key-parameters were defined: (I) drug-specific properties (lipophilicity, solubility), (II) drug-biological properties (fraction unbound, binding partners, clearance) and (III) formulation-dependent factors (dissolution, lag time). The general PBPK modeling workflow was applied as described by Kuepfer et al. (2016) [ 2 ]. Various simulations were performed using different methods for partition coefficient and cellular permeability calculations. Interestingly, the two different extracts led to different PBPK models. The developed adult PBPK models successfully predicted hypericin pharmacokinetics and was extrapolated to pediatric populations following the ICH E11A guideline on pediatric extrapolation [ 3 ]. By predicting age-dependent drug exposure based on physiological differences, the model provides detailed insights into pharmacokinetic variability in adults and children. This approach bridges knowledge gaps, reduces the need for pediatric clinical trials, saves costs, optimizes drug development, and improves availability of evidence-based HMPs for pediatric use [ 4 ] [ 5 ]. Publication History Article published online: 05 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany